It is important to recognize that a depressed mood is not synonymous with a depressive episode. Conversely, an episode of depression may not present with a mood complaint but rather with associated symptoms such as insomnia or other somatic issues. This is particularly true for the elderly and for those seen in primary care settings. Even when a mood complaint is prominent, it may not be described as “depressed,” but instead as “irritable” or “anxious.” Thus, patients may have a variety of problems other than depressed mood, such as insomnia, fatigue, or somatic symptoms. Failure to recognize that MDD underlies these symptoms can lead to unnecessary and costly tests as well as a delay in effective treatment. Complaints may also vary by age group (Table 6-2).

Some patients are first seen with a condition other than MDD (e.g., alcohol abuse), but the history often suggests the possibility of an underlying affective condition. Thus, a positive family history in first-degree relatives or reports consistent with an earlier but apparently resolved depressive episode may be critical to making the proper diagnosis. These patients may also have positive results on certain biological markers associated with MDD which thus far have been primarily employed in research settings, including (15,16,17,18 and 19)

Treatment resistance has been variably defined but typically involves the persistence of a significant depression despite two or more adequate therapeutic trials (20). In this context, there are several issues to consider, including

Obtaining this information is critical, since a substantial proportion of patients may experience poor response due to a variety of factors other than true treatment resistance.

Accurate Diagnosis. Incorrect diagnosis is a common cause for nonresponse to antidepressants. An important issue involves misdiagnosis of the depressive episode as unipolar major depression when the underlying condition is bipolar disorder (particularly type II). In this context, antidepressant-induced “misadventures” may include poor response, worsening of certain symptoms (e.g., agitation, anxiety), or switching into hypomania/mania.

Degree of Resistance. A related question is the degree of treatment resistance. In this context, a number of staging methods are published with the three most frequently employed, including

Comorbidities. Another important factor is the frequency of comorbid conditions which can complicate and compromise adequate response. Disorders that frequently co-occur with major depression include

In addition, more recent data indicate that comorbid social anxiety disorder may predispose to depression recurrence (24).

Associated Symptoms. An important diagnostic issue is psychotic depression (25). Symptoms of psychosis in the context of depression are often subtle and unrecognized. The presence of such symptoms, however, usually predicts a poor response to antidepressant monotherapy as well as an increase in morbidity and mortality (26). Further, melancholic features (e.g., pervasive anhedonia, mood reactivity, psychomotor changes) occur in up to 25% of patients with MDD and may be associated with reduced remission rates, particularly with a selective serotonin reuptake inhibitor (SSRI) (27).

Adequate Treatment Trial. An adequate antidepressant trial may be compromised by subtherapeutic doses. For example, one study (28) found that 60% of elderly depressed patients did not receive antidepressants while in the hospital or on outpatient follow-up (median interval of 45 weeks). Furthermore, most who did receive an antidepressant were usually given inadequate doses.

Time on treatment is another issue. Even though patients can show improvement in 2 to 3 weeks, some may require up to 14 weeks before an adequate response occurs. If, however, there has not been at least partial benefit in 3 to 4 weeks, we recommend pursuing an alternate strategy.

Adherence to Treatment. Nonadherence with the medication regimen is an important factor. A substantial percentage of patients will not sufficiently adhere to treatment, particularly over longer continuation and maintenance periods (29,30 and 31). For certain antidepressants, therapeutic drug monitoring (TDM) can be useful to confirm suspected poor adherence, which the physician can then address with the patient (please see “Adherence” section in Chapter 3).

Level of Recovery. Based on the NIMHsponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, approximately 70% of patients with MDD did not experience a remission after an aggressive trial with citalopram and required additional interventions (32). The implications of unremitted MDD are significant, with over 50% of completed suicides involving a MDE. In addition, a prolonged episode usually has a negative impact on family and other social support systems, career and general health (33). Conversely, significant psychosocial stressors not addressed can contribute to persistent depressive symptomatology despite adequate pharmacological intervention. In such situations, supportive, interpersonal, and cognitive behavioral therapy may be necessary adjuncts to medication. Treatment approaches for inadequate response are discussed in more detail in Chapter 7.

Functional Status and Quality of Life. Increasingly, the focus of effectiveness is shifting from response to remission to recovery. This last issue attempts to translate reduction in symptoms to improved psychosocial interactions and greater satisfaction in life activities (34,35).

The crucial element of both a bipolar and a unipolar disorder is the occurrence of a major affective episode. The critical distinction is that bipolar disorder includes hypomanic/manic, depressive, and mixed episodes, whereas a unipolar disorder includes only depressive episodes. The differential diagnosis proceeds in a stepwise fashion:

Although this differentiation can be difficult and sometimes not possible until hypomania or mania occurs, there are some clues that may help, including

Moreover, hypomania is frequently not viewed as a problem by the patient who is less likely to complain spontaneously about such an episode. Thus, the clinician must be alert for this diagnosis, screen for its occurrence (see discussion of “Mood Disorders Questionnaire” in Chapter 9), and seek collateral information when possible.

It is important to note that the mood disturbance in mania, hypomania, and depression includes the same core symptoms, differing only in the direction of change. Complicating the diagnosis, unipolar patients may also present with melancholia or atypical symptoms. The latter, in particular, can overlap considerably with hypomania.

MDD can present with melancholia, atypical features, or psychosis (delusional depression). These three types have construct validity based on differences in

It is important to recognize these groups because

Melancholia. The features that may distinguish melancholia from the other types of MDD include

This disorder tends to occur most often (but not always) in patients with a positive family history of depression.

Atypical Depression. In this type, the clinical presentation is different from melancholia as follows (37):

In addition, these patients often exhibit rejection hypersensitivity and a “leaden paralysis.” They may be misdiagnosed as having a personality disorder because of the associated irritability and demanding demeanor. Further, the presence of longstanding irritability and hostility may reflect a chronic depressive disorder and not necessarily “character” pathology. With this type of MDD, the patient tends to have a family pattern that has been designated depressive spectrum. Often, first-degree female relatives experience depression, whereas male relatives exhibit alcohol or sedative-hypnotic abuse or other unstable character traits reminiscent of antisocial personality disorder.

Psychotic (Delusional) Depression. Psychotic depression is often characterized by the presence of mood-congruent (i.e., the symptom is consistent with the mood state) delusions or hallucinations. Age of onset tends to follow a bimodal distribution, occurring either in the young or the old. Younger patients often have a family history of bipolar disorder. The female-to-male ratio tends to approximate 1:1. This disorder usually has fewer psychotic symptoms than mania or schizophrenia, most often a single, moodcongruent hallucination or delusion. Often, however, psychotic symptoms are subtle and unrecognized (25). Delusions are more common than hallucinations, which is why the term delusional depression is also used. Whether the patient presents with delusions or hallucinations has no apparent prognostic significance. Examples of delusions commonly found in psychotic depression include the false belief that

The last example is often referred to as a nihilistic delusion, frequently seen in older patients who may even be convinced that their bodies have started to decay. These delusions may be more subtle, particularly in the elderly, appearing as a profound sense of worthlessness and despair. With adequate probing, the delusional quality may become more apparent, facilitating the appropriate therapeutic intervention. When a patient does not benefit from antidepressant monotherapy and demonstrates significant feelings of worthlessness and hopelessness, the possibility of a psychotic MDD should be entertained. Further, even with appropriate treatment, patients with psychotic depression may have a substantially higher frequency of relapse or recurrence, a shorter time to these events, and a higher mortality risk compared with their nonpsychotic counterparts (26,38).

Dysthymic disorder represents a more chronic (i.e., ≥2 years in duration) but less severe form of depression. Depressed mood and partial neurovegetative symptoms are typically present for sustained periods (e.g., years). The major differences between this condition and MDD are the duration of the mood disorder; the usual absence of feelings of low self-esteem, worthlessness and hopelessness; and the absence of a full neurovegetative syndrome. There are still many questions about this condition, including

If the answer to the last question is positive, dysthymia could represent a phenomenon consistent with the concept of “learned helplessness,” which would underscore the importance of early detection and aggressive therapy of MDD.

Patients who meet criteria for both MDD and dysthymic disorder are referred to as having a “double” or “dual” depression. This term, however, should not be used for a first episode until an adequate trial of at least three different classes of antidepressants or two classes of drug and ECT are tried. Retrospective distortion is common in these patients, who may report having always been depressed but remit completely with adequate therapy. Assuming a valid designation of dual depression, most clinicians manage the neurovegetative syndrome with medication while simultaneously using psychotherapeutic approaches specifically developed for mood disorders (e.g., cognitive behavioral or interpersonal psychotherapy).

Comorbid psychiatric symptoms commonly occur with depression. Anxiety symptoms or disorders are most frequently associated with major depression and include (39)

Patients with comorbid anxiety are often more severely depressed and may respond more slowly to treatment compared with those without these symptoms. They are also more likely to have residual pathology and increased rates of relapse and recurrence (40). Many primary care physicians have difficulty distinguishing between depressive and anxiety disorders. This has led to the impression that patients in a general medical setting are more likely to have an admixture of symptoms rather than a clearly defined condition. Making an appropriate diagnosis is also complicated by the minimal psychiatric training they receive and for many at a time when diagnosis was not emphasized.

Although there is considerable overlap in drug therapies for depressive and anxietyrelated disorders, there are also important differences. For example, there is no convincing evidence that benzodiazepines (BZDs) are effective for MDD. Even so, BZDs are often the firstline treatment in the primary care setting for patients with anxiety symptoms, regardless of their psychiatric diagnosis.

Panic Associated with Major Depression. Approximately 25% of patients with major depression have associated past or current panic attacks. The adverse consequences of severe anxiety have been relatively unrecognized, but the possible association between panic symptoms and suicidality dramatically underscores this problem (see Chapter 13). Panic episodes have four major components:

Further, antidepressants can heighten anxiety, irritability, and restlessness especially in the earliest phases of therapy. As a result, it is best to start with low doses (e.g., 5 to 10 mg per day of fluoxetine), gradually titrating upward as tolerated. The judicious use of short-term adjunctive anxiolytics may also be appropriate. Avoiding drugs that lower the threshold for panic symptoms, such as caffeine or over-the-counter stimulants, can also help (see Chapter 7).

Seasonal affective disorder (SAD) is a recurrent depressive illness that regularly coincides with particular seasons (41,42). Such a phenomenon is consistent with the influence of seasonal and other environmental factors on mood, which have been described for more than two millennia. Although the Seasonal Pattern Assessment Questionnaire (SPAQ) has demonstrated validity as a screening instrument to help identify patients with this disorder, its utility and even the construct of SAD as a diagnosis are questioned by some (43,44,45,46 and 47).